From: TSS()Subject: JANUARY 2008 UPDATE ON FEED ENFORCEMENT ACTIVITIES TO LIMIT THE SPREAD OF BSEDate: January 25, 2008 at 9:28 am PST

Friday, January 25, 2008

January 2008 Update on Feed Enforcement Activities to Limit the Spread of BSE

January 24, 2008

Friday, January 25, 2008January 2008 Update on Feed Enforcement Activities to Limit the Spread of BSE

January 24, 2008

January 2008 Update on Feed Enforcement Activities to Limit the Spread of BSE

To help prevent the establishment and amplification of Bovine Spongiform Encephalophathy (BSE) through feed in the United States, the Food and Drug Administration (FDA) implemented a final rule that prohibits the use of most mammalian protein in feeds for ruminant animals. This rule, Title 21 Part 589.2000 of the Code of Federal Regulations, here called the Ruminant Feed Ban, became effective on August 4, 1997.

The following is an update on FDA enforcement activities regarding the ruminant feed ban. FDA's Center for Veterinary Medicine (CVM) has assembled data from the inspections that have been conducted AND whose final inspection report has been recorded in the FDA's inspection database as of January 12, 2008. As of January 12, 2008, FDA had received over 59,000 inspection reports. The majority of these inspections (approximately 70%) were conducted by State feed safety officials, with the remainder conducted by FDA officials.

Inspections conducted by FDA or State investigators are classified to reflect the compliance status at the time of the inspection based upon the objectionable conditions documented. These inspection conclusions are reported as Official Action Indicated (OAI), Voluntary Action Indicated (VAI), or No Action Indicated (NAI).

An OAI inspection classification occurs when significant objectionable conditions or practices were found and regulatory sanctions are warranted in order to address the establishment's lack of compliance with the regulation. An example of an OAI inspection classification would be findings of manufacturing procedures insufficient to ensure that ruminant feed is not contaminated with prohibited material. Inspections classified with OAI violations will be promptly re-inspected following the regulatory sanctions to determine whether adequate corrective actions have been implemented.

A VAI inspection classification occurs when objectionable conditions or practices were found that do not meet the threshold of regulatory significance, but do warrant advisory actions to inform the establishment of findings that should be voluntarily corrected. Inspections classified with VAI violations are more technical violations of the Ruminant Feed Ban. These include provisions such as minor recordkeeping lapses and conditions involving non-ruminant feeds.

An NAI inspection classification occurs when no objectionable conditions or practices were found during the inspection or the significance of the documented objectionable conditions found does not justify further actions.

The results to date are reported here both by “segment of industry” and “in total”. NOTE – A single firm can operate as more than one firm type. As a result, the categories of the different industry segments are not mutually exclusive.

RENDERERS

These firms are the first to handle and process (i.e., render) animal proteins and to send these processed materials to feed mills and/or protein blenders for use as a feed ingredient.

Number of active firms whose initial inspection has been reported to FDA – 267

Number of active firms handling materials prohibited from use in ruminant feed – 165 (62 % of those active firms inspected)

FDA licenses these feed mills to produce medicated feed products. The license is required to manufacture and distribute feed using certain potent drug products, usually those requiring some pre-slaughter withdrawal time. This licensing has nothing to do with handling prohibited materials under the feed ban regulation. A medicated feed license from FDA is not required to handle materials prohibited under the Ruminant Feed Ban.

Number of active firms whose initial inspection has been reported to FDA – 1,077

Number of active firms handling materials prohibited from use in ruminant feed – 473 (44 % of those active firms inspected)

Note that a single firm can be reported under more than one firm category; therefore, the summation of the individual OAI/VAI firm categories will be more than the actual total number of OAI/VAI firms, as presented below.

Number of active firms whose initial inspection has been reported to FDA – 21,630

Number of active firms handling materials prohibited from use in ruminant feed – 6,927 (32 % of those active firms inspected)

Date: March 21, 2007 at 2:27 pm PSTRECALLS AND FIELD CORRECTIONS: VETERINARY MEDICINES -- CLASS II___________________________________PRODUCTBulk cattle feed made with recalled Darling’s 85% Blood Meal, Flash Dried,Recall # V-024-2007CODECattle feed delivered between 01/12/2007 and 01/26/2007RECALLING FIRM/MANUFACTURERPfeiffer, Arno, Inc, Greenbush, WI. by conversation on February 5, 2007.Firm initiated recall is ongoing.REASONBlood meal used to make cattle feed was recalled because it wascross-contaminated with prohibited bovine meat and bone meal that had beenmanufactured on common equipment and labeling did not bear cautionary BSEstatement.VOLUME OF PRODUCT IN COMMERCE42,090 lbs.DISTRIBUTIONWI

The etiology of sporadic Creutzfeldt-Jakob disease (sCJD), the most frequent humanprion disease, remains still unknown. The marked disease phenotype heterogeneityobserved in sCJD is thought to be influenced by the type of proteinase K-resistantprion protein, or PrPSc (type 1 or type 2 according to the electrophoretic mobility ofthe unglycosylated backbone), and by the host polymorphic Methionine/Valine (M/V)codon 129 of the PRNP. By using a two-dimensional gel electrophoresis (2D-PAGE)and imunoblotting we previously showed that in sCJD, in addition to the PrPSc type,distinct PrPSc C-terminal truncated fragments (CTFs) correlated with different sCJDsubtypes. Based on the combination of CTFs and PrPSc type, we distinguished threePrPSc patterns: (i) the first was observed in sCJD with PrPSc type 1 of all genotypes,;(ii) the second was found in M/M-2 (cortical form); (iii) the third in amyloidogenic M/V-2 and V/V-2 subtypes (Zanusso et al., JBC 2004) . Recently, we showed that sCJDsubtype M/V-2 shared molecular and pathological features with an atypical form ofBSE, named BASE, thus suggesting a potential link between the two conditions. Thisconnection was further confirmed after 2D-PAGE analysis, which showed an identicalPrPSc signature, including the biochemical pattern of CTFs. To pursue this issue, weobtained brain homogenates from Cynomolgus macaques intracerebrally inoculatedwith brain homogenates from BASE. Samples were separated by using a twodimensional electrophoresis (2D-PAGE) followed by immunoblotting. We here showthat the PrPSc pattern obtained in infected primates is identical to BASE and sCJDMV-2 subtype. These data strongly support the link, or at least a common ancestry,between a sCJD subtype and BASE.

This work was supported by Neuroprion (FOOD-CT-2004-506579)

FC5.5.2

Transmission of Italian BSE and BASE Isolates in Cattle Results into a TypicalBSE Phenotype and a Muscle Wasting Disease

The clinical phenotype of bovine spongiform encephalopathy has been extensivelyreported in early accounts of the disorder. Following the introduction of statutory activesurveillance, almost all BSE cases have been diagnosed on a pathological/molecularbasis, in a pre-symptomatic clinical stage. In recent years, the active surveillancesystem has uncovered atypical BSE cases, which are characterized by distinctconformers of the PrPSc, named high-type (BSE-H) and low-type (BSE-L), whoseclinicopathological phenotypes remain unknown. We recently reported twoItalian atypical cases with a PrPSc type similar to BSE-L, pathologically characterized by PrP amyloid plaques. Experimental transmission to TgBov mice has recentlydisclosed that BASE is caused by a distinct prion strain which is extremely virulent. Amajor limitation of transmission studies to mice is the lack of reliable information onclinical phenotype of BASE in its natural host. In the present study, we experimentallyinfected Fresian/Holstein and Alpine/Brown cattle with Italian BSE and BASE isolatesby i.c. route. BASE infected cattle showed survival times significantly shorter thanBSE, a finding more readily evident in Fresian/Holstein, and in keeping with previousobservations in TgBov mice. Clinically, BSE-infected cattle developed a diseasephenotype highly comparable with that described in field BSE cases and inexperimentally challenged cattle. On the contrary, BASE-inoculated cattledeveloped an amyotrophic disorder accompanied by mental dullness.The molecular and neuropathological profiles, including PrP deposition pattern, closelymatched those observed in the original cases. This study further confirms that BASEis caused by a distinct prion isolate and discloses a novel disease phenotype in cattle,closely resembling the phenotype previous reported in scrapie-inoculated cattle and insome subtypes of inherited and sporadic Creutzfeldt-Jakob disease.

In 2001, a study was initiated in primates to assess the risk for humansto contract BSE through contaminated food. For this purpose, BSE brain wastitrated in cynomolgus monkeys.

Aims:

The primary objective is the determination of the minimal infectious dose (MID50)for oral exposure to BSE in a simian model, and, by in doing this, to assess the risk forhumans. Secondly, we aimed at examining the course of the disease to identifypossible biomarkers.

Methods:

Groups with six monkeys each were orally dosed with lowering amounts ofBSE brain: 16g, 5g, 0.5g, 0.05g, and 0.005g. In a second titration study,animals were intracerebrally (i.c.) dosed (50, 5, 0.5, 0.05, and 0.005 mg).

Results:

In an ongoing study, a considerable number of high-dosed macaques alreadydeveloped simian vCJD upon oral or intracerebral exposure or are at theonset of the clinical phase. However, there are differences in the clinical coursebetween orally and intracerebrally infected animals that may influence the detection of biomarkers.

Conclusions:

Simian vCJD can be easily triggered in cynomolgus monkeys on the oralroute using less than 5 g BSE brain homogenate. The difference in theincubation period between 5 g oral and 5 mg i.c. is only 1 year (5 years versus 4years). However, there are rapid progressors among orally dosed monkeys that develop simian vCJD as fast as intracerebrally inoculated animals.

The work referenced was performed in partial fulfilment of the study “BSE inprimates“ supported by the EU (QLK1-2002-01096).

http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf

ALSO, look at the table and you'll see that as little as 1 mg (or 0.001 gm) caused 7% (1 of 14) of the cows to come down with BSE;

The uncertain extent of human exposure to bovine spongiformencephalopathy (BSE)--which can lead to variant Creutzfeldt-Jakob disease(vCJD)--is compounded by incomplete knowledge about the efficiency of oralinfection and the magnitude of any bovine-to-human biological barrier totransmission. We therefore investigated oral transmission of BSE tonon-human primates. We gave two macaques a 5 g oral dose of brain homogenatefrom a BSE-infected cow. One macaque developed vCJD-like neurologicaldisease 60 months after exposure, whereas the other remained free of diseaseat 76 months. On the basis of these findings and data from other studies, wemade a preliminary estimate of the food exposure risk for man, whichprovides additional assurance that existing public health measures canprevent transmission of BSE to man.

The comparison is made on the basis of calibration of the bovine inoculumused in our study with primates against a bovine brain inoculum with asimilar PrPres concentration that was

inoculated into mice and cattle.8 *Data are number of animalspositive/number of animals surviving at the time of clinical onset ofdisease in the first positive animal (%). The accuracy of

bioassays is generally judged to be about plus or minus 1 log. icip=intracerebral and intraperitoneal.

Table 1: Comparison of transmission rates in primates and cattle infectedorally with similar BSE brain inocula

Published online January 27, 2005

http://www.thelancet.com/journal/journal.isa

It is clear that the designing scientists must

also have shared Mr Bradley’s surprise at the results because all the dose

levels right down to 1 gram triggered infection.

http://www.bseinquiry.gov.uk/files/ws/s145d.pdf

6. It also appears to me that Mr Bradley’s answer (that it would take lessthan say 100 grams) was probably given with the benefit of hindsight; particularly if one considers that later in the same answer Mr Bradley expresses his surprisethat it could take as little of 1 gram of brain to cause BSE by the oral routewithin the same species. This information did not become available until the "attackrate" experiment had been completed in 1995/96. This was a titration experimentdesigned to ascertain the infective dose. A range of dosages was used toensure that the actual result was within both a lower and an upper limit within thestudy and the designing scientists would not have expected all the dose levels totrigger infection. The dose ranges chosen by the most informed scientists at thattime ranged from 1 gram to three times one hundred grams. It is clear that thedesigning scientists must have also shared Mr Bradley’s surprise at the resultsbecause all the dose levels right down to 1 gram triggered infection.